2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-PGI1 compounds

ABSTRACT

The present invention relates to certain structural and pharmacological analogs of prostacyclin (PGI 2 ) which are 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-PGI 1  compounds. These novel pharmacological agents are useful as smooth muscle stimulators.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of Serial No. 821,542, filed Aug. 3, 1977, now U.S. Pat. No. 4,154,676.

The present invention relates to novel 2-decarboxy-2-aminomethyl-trans-4,5-didehydro-PGI₁ compounds, the essential material constituting a disclosure of the preparation and use thereof is incorporated here by reference from U.S. Pat. No. 4,109,082, issued Aug. 22, 1978.

The present invention particularly relates to the following compounds:

2-Decarboxy-2-aminomethyl-(6RS)-trans-4,5-didehydro-PGI₁ ;

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-6α-PGI₁ ;

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-6α-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-6α-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-6α-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-6β-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-6.beta.-PGI₁ ;

2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-6β-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-6β-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-6(RS)-trans-4,5-didehydro-cis-13-PGI₁ ;

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-cis-13,6α-PGI₁ :

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-cis-13-6α-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-cis-13-6.alpha.-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-cis-13-6.alpha.-PGI₁ ;

2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-cis-13-6β-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-cis-13-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-6(RS)-trans-4,5-didehydro-13,14-dihydro-PGI₁ ;

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-13,14-dihydro-6α-PGI.sub.1 ;

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-13,14-dihydro-6.alpha.-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁ ;

2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-13,14-dihydro-6.beta.-PGI₁ ;

2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-13,14-dihydro-6.beta.-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁ ;

2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁ ; and

2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-13,14-dihydro-6β-PGI.sub.1. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein Y₂ is trans--CH═CH--, cis--CH═CH--, or --CH₂ CH₂ --;wherein Z₂ is ##STR2## wherein Z₁ is (1) --(CH₂)_(g) --CH₂ --CH₂ --, or (2) --(CH₂)_(g) --CH₂ --CF₂ --, wherein g is the integer zero, one, or 2; wherein R₈ is hydrogen, hydroxy, or hydroxymethyl; wherein M₁ is ##STR3## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive; and wherein L₁ is ##STR4## or a mixture of ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein L₂ and L₃ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; and wherein R₇ is (1) --(CH₂)_(m) --CH₃, ##STR6## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two T's are other than alkyl.
 2. A prostacyclin analog according to claim 1, wherein Y₂ is trans--CH═CH--.
 3. A prostacyclin analog according to claim 2, wherein Z₂ is a mixture of ##STR7##
 4. 2-Decarboxy-2-aminomethyl-(6RS)-trans-4,5-didehydro-PGI₁, a prostacyclin analog according to claim
 3. 5. A prostacyclin analog according to claim 2, wherein Z₂ is ##STR8##
 6. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 5. 7. 2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 5. 8. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 5. 9. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 5. 10. A prostacyclin analog according to claim 2, wherein Z₂ is ##STR9##
 11. A prostacyclin analog according to claim 10, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --.
 12. 2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 11. 13. A prostacyclin analog according to claim 10, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 14. A prostacyclin analog according to claim 13, wherein g is zero.
 15. A prostacyclin analog according to claim 14, wherein R₇ is ##STR10##
 16. 2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 15. 17. A prostacyclin analog according to claim 14, wherein R₇ is ##STR11##
 18. 2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 17. 19. A prostacyclin analog according to claim 14, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 20. A prostacyclin analog according to claim 19, wherein R₅ is methyl.
 21. 2-Decarboxy-2-amino methyl-15-methyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 22. A prostacyclin analog according to claim 19, wherein R₅ is hydrogen.
 23. A prostacyclin analog according to claim 22, wherein at least one of R₃ and R₄ is fluoro.
 24. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 23. 25. A prostacyclin analog according to claim 22, wherein at least one of R₃ and R₄ is methyl.
 26. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 25. 27. A prostacyclin analog according to claim 22, wherein R₃ and R₄ are both hydrogen.
 28. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 27. 29. A prostacyclin analog according to claim 1, wherein Y₂ is cis--CH═CH--.
 30. A prostacyclin analog according to claim 29, wherein Z₂ is a mixture of ##STR12##
 31. 2-Decarboxy-2-aminomethyl-6(RS)-trans-4,5-didehydro-cis-13-PGI₁, a prostacyclin analog according to claim
 30. 32. A prostacyclin analog according to claim 29, wherein Z₂ is ##STR13##
 33. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-cis-13-6α-PGI₁, a prostacyclin analog according to claim
 32. 34. 2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-cis-13-6α-PGI₁, a prostacyclin analog according to claim
 32. 35. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-cis-13-6β-PGI.sub.1, a prostacyclin analog according to claim
 32. 36. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-cis-13-6α-PGI₁, a prostacyclin analog according to claim
 32. 37. A prostacyclin analog according to claim 29, wherein Z₂ is ##STR14##
 38. A prostacyclin analog according to claim 37, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --.
 39. 2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 38. 40. A prostacyclin analog according to claim 37, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 41. A prostacyclin analog according to claim 40, wherein g is zero.
 42. A prostacyclin analog according to claim 41, wherein R₇ is ##STR15##
 43. 2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 42. 44. A prostacyclin analog according to claim 41, wherein R₇ is ##STR16##
 45. 2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 44. 46. A prostacyclin analog according to claim 41, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 47. A prostacyclin analog according to claim 46, wherein R₅ is methyl.
 48. 2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 47. 49. A prostacyclin analog according to claim 46, wherein R₅ is hydrogen.
 50. A prostacyclin analog according to claim 49, wherein at least one of R₃ and R₄ is fluoro.
 51. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 50. 52. A prostacyclin analog according to claim 49, wherein at least one of R₃ and R₄ is methyl.
 53. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 52. 54. A prostacyclin analog according to claim 49, wherein R₃ and R₄ are both hydrogen.
 55. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-cis-13-6β-PGI₁, a prostacyclin analog according to claim
 54. 56. A prostacyclin analog according to claim 1, wherein Y₂ is --CH₂ CH₂ --.
 57. A prostacyclin analog according to claim 56, wherein Z₂ is a mixture of ##STR17##
 58. 2-Decarboxy-2-aminomethyl-6(RS)-trans-4,5-didehydro-13,14-dihydro-PGI.sub.1, a prostacyclin analog according to claim
 57. 59. A prostacyclin analog according to claim 56, wherein Z₂ is ##STR18##
 60. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁, a prostacyclin analog according to claim
 59. 61. 2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁, a prostacyclin analog according to claim
 59. 62. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁, a prostacyclin analog according to claim
 59. 63. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-13,14-dihydro-6α-PGI₁, a prostacyclin analog according to claim
 59. 64. A prostacyclin analog according to claim 56, wherein Z₂ is ##STR19##
 65. A prostacyclin analog according to claim 64, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --.
 66. 2-Decarboxy-2-aminomethyl-2,2-difluoro-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 65. 67. A prostacyclin analog according to claim 64, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 68. A prostacyclin analog according to claim 67, wherein g is zero.
 69. A prostacyclin analog according to claim 68, wherein R₇ is ##STR20##
 70. 2-Decarboxy-2-aminomethyl-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 69. 71. A prostacyclin analog according to claim 68, wherein R₇ is ##STR21##
 72. 2-Decarboxy-2-aminomethyl-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 71. 73. A prostacyclin analog according to claim 68, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 74. A prostacyclin analog according to claim 73, wherein R₅ is methyl.
 75. 2-Decarboxy-2-aminomethyl-15-methyl-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 74. 76. A prostacyclin analog according to claim 73, wherein R₅ is hydrogen.
 77. A prostacyclin analog according to claim 76, wherein at least one of R₃ and R₄ is fluoro.
 78. 2-Decarboxy-2-aminomethyl-16,16-difluoro-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 77. 79. A prostacyclin analog according to claim 76, wherein at least one of R₃ and R₄ is methyl.
 80. 2-Decarboxy-2-aminomethyl-16,16-dimethyl-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 79. 81. A prostacyclin analog according to claim 76, wherein R₃ and R₄ are both hydrogen.
 82. 2-Decarboxy-2-aminomethyl-trans-4,5-didehydro-13,14-dihydro-6β-PGI₁, a prostacyclin analog according to claim
 81. 